Volume 213 - Issue 8
Should patients with heart failure listen to their gut?
Authors: John J Atherton and Chamindie Punyadeera
Med J Aust 2020; 213 (8): 357-358. || doi: 10.5694/mja2.50797
Published online: 19 October 2020
Published online: 19 October 2020
Dysregulation of the gut microbiota may be a target for novel therapeutic approaches
Dysregulation of the gut microbiota may be a target for novel therapeutic approaches
Large randomised, controlled studies have found that modulating dysregulated neurohormonal systems in patients with heart failure can reduce morbidity and mortality in those with a reduced left ventricular ejection fraction (LVEF).1 However, long term clinical outcomes remain poor, and most patients are unable to achieve the target doses of guideline‐directed therapy. Further, these drugs do not resolve all the pathophysiological perturbations associated with heart failure. Interest in biomarker discovery is therefore growing, not only to facilitate earlier diagnosis and risk stratification, but also to identify novel targets for therapeutic interventions.
One potential target is the gut microbiota, comprising trillions of microorganisms encoding more than three million genes and producing thousands of metabolites.2 The relationship of the microbiota with the host is generally symbiotic; for example, they ferment indigestible fibres needed for the production of short chain fatty acids and synthesise secondary bile acids. Systemic hypoperfusion and splanchnic congestion in patients with heart failure may increase intestinal permeability, allowing bacterial translocation and leading to elevated plasma endotoxin levels.3 This may stimulate the production of inflammatory cytokines associated with poorer outcomes for people with heart failure.4 However, the results of anti‐cytokine interventions have thus far proved disappointing.5
More recent studies have investigated whether dysregulation of the gut microbiota (dysbiosis) and downstream active metabolites could play an active role in the development and progression of cardiovascular disease. Unbiased metabolomic discovery studies conducted more than a decade ago suggested that the trimethylamine–trimethylamine N‐oxide (TMAO) pathway could be a target.6 Gut bacteria generate trimethylamine from dietary choline, phosphatidylcholine and l‐carnitine, which are abundant in red meat, deep sea fish, poultry, and eggs. Trimethylamine enters the portal circulation and is converted to TMAO in the liver. TMAO levels are increased in patients with heart failure,7 and its levels are higher in patients with more advanced heart failure,8 but its clinical relevance has been unclear.
This issue of the MJA includes a systematic review by Li and colleagues of seven prospective studies that explored the association between TMAO and major adverse cardiac events (MACEs) in a total of 6879 patients with heart failure.9 After adjusting for other cardiovascular risk factors, they found that the risk of MACEs was 68% higher and that of all‐cause mortality 67% higher for patients with TMAO levels in the highest tertile compared with patients in the lowest tertile. While these findings are largely consistent with those of the individual studies, the systematic review provides greater confidence in the clinical validity of TMAO as a prognostic biomarker for heart failure, and similar findings have been reported for other populations.6,10 The association between plasma TMAO and MACE risk remained significant in analyses adjusted for renal function. This suggests that higher TMAO levels are not solely attributable to reduced renal excretion in patients with more severe heart failure and that gut dysbiosis may contribute to poorer outcomes.
The strengths of the study by Li and colleagues include the selective inclusion of prospective studies with hard clinical endpoints, with median follow‐up of five years. However, many questions remain unanswered. Do these findings apply to all heart failure phenotypes? With one exception, the included studies enrolled patients with chronic heart failure. Preliminary analyses suggest that plasma TMAO may be a stronger predictor of outcomes for patients with heart failure and reduced LVEF than for patients with relatively preserved LVEF.8 Further studies of patients with acute heart failure and exploring whether risk varies according to LVEF are required. As mentioned by Li and his co‐authors, it is also unclear if ethnic background or diet are important risk factors. Whether changes in TMAO levels over time provide incremental risk prediction information also needs to be explored.8
The key question is whether TMAO is a risk marker or a modifiable risk factor. A mechanistic link has been suggested by animal studies. Dietary supplementation with choline or TMAO has pro‐thrombotic and atherogenic effects6,11 that can be abrogated by antibiotic suppression of the intestinal flora.6 In a pressure overload heart failure model, choline and TMAO supplementation led to higher rates of pulmonary oedema, left ventricular systolic dysfunction, and myocardial fibrosis.12 Inhibiting TMAO production prevented (in a Western diet‐induced obesity mouse model13) or ameliorated (in a post‐myocardial infarction heart failure model14) myocardial dysfunction.
The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) investigators reported that B‐type natriuretic peptide levels fell with guideline‐directed therapy, but TMAO levels were not only unchanged but remained predictive of poorer outcomes.8 This suggests that the pathophysiological link between TMAO level and adverse outcomes in heart failure is not influenced by our current therapies. While a recent small study reported reduced left atrial diameter following probiotic therapy in patients with heart failure and reduced LVEF,15 larger clinical intervention studies, such as the ongoing GutHeart study,16 are needed to determine whether manipulating the gut microbiota or removing downstream metabolites improves clinical outcomes.
So patients with heart failure should perhaps listen to their gut, and in the future we may add eubiotic therapies to our armamentarium for treating heart failure.
Competing interests
No relevant disclosures.
References
- Atherton JJ, Sindone A, De Pasquale CG, et al. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of heart failure 2018. Med J Aust 2018; 209: 363–369. https://www.mja.com.au/journal/2018/209/8/national-heart-foundation-australia-and-cardiac-society-australia-and-new-0
- Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol 2019; 16: 137–154.
- Niebauer J, Volk HD, Kemp M, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999; 353: 1838–1842.
- Rauchhaus M, Doehner W, Francis DP, et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000; 102: 3060–3067.
- Hartman MHT, Groot HE, Leach IM, et al. Translational overview of cytokine inhibition in acute myocardial infarction and chronic heart failure. Trends Cardiovasc Med 2018; 28: 369–379.
- Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472: 57–63.
- Tang WH, Wang Z, Fan Y, et al. Prognostic value of elevated levels of intestinal microbe‐generated metabolite trimethylamine‐N‐oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol 2014; 64: 1908–1914.
- Suzuki T, Yazaki Y, Voors AA, et al. Association with outcomes and response to treatment of trimethylamine N‐oxide in heart failure: results from BIOSTAT‐CHF. Eur J Heart Fail 2019; 21: 877–886.
- Li W, Huang A, Zhu H, et al. Gut microbiota‐derived trimethylamine N‐oxide is associated with poor prognosis in patients with heart failure. Med J Aust 2020; 213: 374–379.
- Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013; 368: 1575–1584.
- Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 2016; 165: 111–124.
- Organ CL, Otsuka H, Bhushan S, et al. Choline diet and its gut microbe‐derived metabolite, trimethylamine N‐oxide, exacerbate pressure overload‐induced heart failure. Circ Heart Fail 2016; 9: e002314.
- Chen K, Zheng X, Feng M, et al. Gut microbiota‐dependent metabolite trimethylamine N‐oxide contributes to cardiac dysfunction in western diet‐induced obese mice. Front Physiol 2017; 8: 139.
- Li X, Sun Y, Zhang X, Wang J. Reductions in gut microbiota‐derived metabolite trimethylamine N‐oxide in the circulation may ameliorate myocardial infarction‐induced heart failure in rats, possibly by inhibiting interleukin‐8 secretion. Mol Med Rep 2019; 20: 779–786.
- Costanza AC, Moscavitch SD, Faria Neto HC, Mesquita ET. Probiotic therapy with Saccharomyces boulardii for heart failure patients: a randomized, double‐blind, placebo‐controlled pilot trial. Int J Cardiol 2015; 179: 348–350.
- Mayerhofer CCK, Awoyemi AO, Moscavitch SD, et al. Design of the GutHeart‐targeting gut microbiota to treat heart failure‐trial: a phase II, randomized clinical trial. ESC Heart Fail 2018; 5: 977–984.
Provenance: Commissioned; externally peer reviewed.